Management of Multiple Myeloma: The Changing Paradigm

Myeloma 101: Disease Overview

Craig Emmitt Cole, MDUniversity of Michigan Comprehensive Cancer Center

Red Blood Cells

White Blood Cells

Platelet Cells

Bone Marrow Stem Cell

LymphGlands

Lymph Cells

PlasmaCells

Antibody Proteins

Bone MarrowBlood Factory

Anatomy and Biology (just a little….)What are Blood Cancers, What IS Multiple

Myeloma?

Antibody Proteins

Bone MarrowBlood Factory

Red Blood Cells

White Blood Cells

Platelet Cells

LymphGlands

Lymph Cells

PlasmaCells

Bone Marrow Stem Cell

LYMPHOMA

LEUKEMIA

MULTIPLE MYELOMAMonoclonalM-proteins

Lightchains

Antibody Anatomy

HeavychainsFree Light Chains

Multiple Myeloma Today

CML, chronic myeloid leukemia; CLL, chronic lymphocytic leukemia; MM, multiple myeloma; NHL, non-Hodgkin lymphoma.Leukemia & Lymphoma Society. Facts 2014-2015. Available at: http://www.lls.org/#/resourcecenter/freeeducationmaterials/generalcancer/facts. Accessed April 6, 2015. Siegel RL et al. CA Cancer J Clin. 2016;66:7.

Multiple Myeloma and Common Symptoms

About 10% to 20% of patients with newly diagnosed myeloma will

not have any symptoms.

Low Blood Counts• Anemia is present in 60%

at diagnosis• May lead to anemia and

infection

WeaknessFatigueInfection

Decreased Kidney Function• Occurs in over half of

myeloma patients

Bone Damage• Affects 85% of patients• Leads to fractures

Bone Turnover• Leads to high levels of

calcium in blood (hypercalcemia)

Weakness

Bone pain

Loss of appetite

Weight loss

Multiple Myeloma Complications. http://www.themmrf.org/multiple-myeloma/multiple-myeloma-complicationsAccessed April 14, 2016.Campbell K. Nurs Times. 2014;110:12.

Key Steps to Takeon Your Journey

Laboratory tests and diagnosis

Staging and prognosis

Obtain a second opinion

Treatment

The promise of precision medicine

Diagnosing Myeloma: Learn Your Labs!

CBC • Number of red blood cells, white blood cells, and platelets

CoMP• Measure levels of albumin, calcium, lactate dehydrogenase

[LDH], blood urea nitrogen [BUN], and creatinine. Assess function of kidney, liver, and bone status and the extent of disease.

Beta2MicroG

• Determine the level of a protein that indicates the presence/extent of MM and kidney function

IFE • Identify the type of abnormal antibody proteins: IgG, IgA, κ,or λ

SPEP • Detect the presence and level of M protein

SFLC • Freelite® test measures free light chains (kappa or lambda) in blood

UPEP • Detect Bence-Jones proteins (otherwise known as myeloma light chains) in Urine

24-hr Urine

Analysis• Determine the presence and levels of M protein and Bence Jones

protein in the Urine

CBC, complete blood count; CMP, complete metabolic panel; B2M; beta-2 microglobulin; SPEP, serum protein electrophoresis;IFE, immunofixation electrophoresis; SFLC, serum free light chain assay; UPEP, urine protein electropheresis;

Blood and Urine Tests

Q: Where Do We Start Lookingfor Myeloma?

A: Monoclonal Protein!

Albuminγ ZoneProteins

α ZoneProteins

β ZoneProteins

Plasma Cells

Lightest Heaviest

IgGIgGIgG IgAIgAIgA IgMIgMIgM

Serum Protein ElectrophoresisNormal

Antibodies

Plasma

γ ZoneProteinsAlbumin

α ZoneProteins

β ZoneProteins

Monoclonal Plasma Cells

Lightest Heaviest

Serum Protein ElectrophoresisMonoclonal Gammopathy

Plasma

Monoclonal protein

IgGKappa

M-Protein

IgGKappa

M-Protein

Treatment

γ ZoneProteinsAlbumin

α ZoneProteins

β ZoneProteins

Monoclonal Plasma Cells

Lightest Heaviest

Serum Protein ElectrophoresisMonoclonal Gammopathy Light Chains

Plasma

Monoclonal protein

Monoclonal Light Chain

protein

• Serum free light chains (FLC) blood test uses κ and λantibodies against specific areas that are exposed on FLCs.

• FLCs independently quantify the two light chain types.

• Clonality can be identified by the demonstration of an abnormal ratio of κ : λ FLCs.

Normal Range

κ light-chain-only multiple myeloma

λ light-chain-only multiple myeloma

Hutchison, C. A. et al. (2009) Serum free light chain assessment in monoclonal gammopathy and kidney disease Nat. Rev. Nephrol. doi:10.1038/nrneph.2009.151

Light Chain Monoclonal GammopathyDetection: Serum Free Light Chains

• In 17% of patients with myeloma only produce a light chains.

KappaLt.

Chain

LambdaLt.

Chain

KappaLt.

Chain

LambdaLt.

Chain

Ratio: 1Ratio: 1.06

Light Chain Monoclonal Gammopathy

NormalNormalwith inflammation

1.00mg/dL 1.00mg/dL1.80mg/dL 1.70mg/dL

Ratio: 1.06

Light Chain Monoclonal Gammopathy

LambdaLt.

Chain

KappaLt.

Chain

KappaLt.

ChainMM

Ratio: >100Positive Kappa Monoclonal Serum Light Chains

Normalwith inflammation

178.80mg/dL 0.50mg/dL

KappaLt.

Chain LambdaLt.

Chain

Light Chain Monoclonal Gammopathy

1.00mg/dL 1.00mg/dL

KappaLt.

Chain

After therapy of MMRestore normal Light Chains

Ratio:100Ratio:1

Diagnosing Myeloma: Know Your Imaging Tests!

X-ray MRI CT scan PET scan

Conventional x-rays reveal punched-out lytic lesions, osteoporosis, or fractures in 75% of

patients.

MRI & PET/CT appear to be more sensitive (85%) than skeletal x-rays for the detection of small lytic bone lesions.

Assess changes in the bone structure and determine the number and size of tumors in the bone

Diagnosing Myeloma: Know Your Bone Marrow Tests!

Karyotyping

FISH (fluorescence in situ hybridization)

MM cell

Chromosome

Jamshidi needle

Bone marrow

Skin

Hip bone

Bone Marrow Aspiration and

Biopsy

Cytogenetic Analysis

What’s inside those Myeloma Cells:FISH (fluorescence in situ hybridization)

Chromosome 7

Serum levels of 2 –Microglobulin are of Prognostic Importance in Myeloma

2 –Microglobulin

The higher the 2 Microglobulin = the more plasma cells and/or the

worse the kidney function.

Putting the Results Together

Staging and Prognosis

Bone marrow analysis

Bone marrow analysis

Imaging resultsImaging results

Blood and urine

test results

Blood and urine

test results

Stage IIIStage II

Multiple Myeloma Staging

Greipp PR et al. J Clin Oncol. 2005;23:3412.

β2 –MicroglobulinB2M

Stage I

Albumin3.5 g/dL

B2M <3.5 mg/dL B2M >5.5Neither stage I

nor stage III

High Risk Intermediate Risk Standard Risk

How Aggressive Is My Myeloma?

*Based on the Updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Guidelines 2013Mikhael JR et al. Mayo Clin Proc. 2013;88:360.

0

60

40

80

20

Risk Level* (Degree of Aggressiveness)

3 4–5 10Survival (years)

FISH• del 17p• t(14;16)• t(14;20)

GEP• High-risk signature

FISH• t(4;14)*

Cytogenetic• del 13 or hypodiploid• PCLI ≥3%

All others including:• Hyperdiploid• t(11;14)• t(6;14)

Pat

ient

s af

fect

ed (%

)

Revised International Staging System for Multiple Myeloma

Prognostic Factor Stage I Stage II Stage IIIISS Stage• I -Serum β2-microglobulin <3.5 mg/L, serum

albumin >3.5 g/dL• II- Not ISS stage I or III• III- Serum 2-microglobulin >5.5 mg/L

ISS Stage I ISS Stage II ISS Stage III

AND/OR AND AND

LDHNormal Serum LDH: <the upper limit of normalHigh Serum LDH: > the upper limit of normal

Normal High

AND/OR AND AND/OR

Cytogenetic*High Risk:

• del(17p) • t(4;14) • t(14;16)

Standard risk No high-risk CA

No high Risk High Risk

*Based on the Updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Guidelines 2013 Mikhael JR et al. Mayo Clin Proc. 2013;88:360.

Not R-ISS Stage I or III

Palumbo et al. JCO. September 10, 2015 vol. 33 no. 26 2863-2869

The Promise of Precision Medicine…

Starts With Genomics

How Do We Match the Right Myeloma Medicines to Each Patient?

Precision Medicine

• Gene expressionprofiling [GEP]

• Whole-genome/ whole-exomesequencing)

• Next-generation sequencing

MM cell

Chromosome

DNA

Personalizing medical care with DNA testing of many different genes (genomics) at the same time

Genomictesting

Tailoredtreatment

Bone marrow tissue samplesNewly diagnosed → relapse

MMRF CoMMpassSM Study: Advancing Personalized

Medicine Research• Landmark study focusing

on the genomics of myeloma

• Goals: – Learn which patients

respond best to which therapies

– Achieve better treatments targeted to each patient’s biological makeup

• 1,000 newly diagnosed patients will be followed for at least 10 years

For more information call the MMRF at 866-603-6628

or visit www.themmmrf.org.

Enrollment complete!

Interpreting results

Interpreting results

Know Your Myeloma Genomics

Tissue banking

(NDMM to RRMM)

Tissue banking

(NDMM to RRMM)

What tests are available?

What tests are available?

Is it available to me?

Is it available to me?

MGUS or Smoldering Myeloma

Active myeloma

Up Front Therapy

PlateauRemission

Asymptomatic

Relapse

Salvage Therapy

RefractoryTherapy

Symptomatic

BriefPlateau

Relapse

Refractory Relapse

ProgressiveMyeloma

Time

Dis

ease

Bur

den

(M-P

rote

in)

The Typical Course of Myeloma

• Auto Transplant• Novel Therapies• Maintenance Therapy

No anemia or bone lesions.

Normal calcium levels and

kidney function.

Possible anemia, bone lesions, high calcium levels, or reduced kidney function.

Myeloma is not

responsive to therapy.

0

2

4

6

IgGKappa

M-Protein

After Establishing a MM Diagnosis, Find Out From Your Doctor...

IgGKappa

M-Protein

What is your response to

therapy?

Treatment

Treatment Overview

Overview of Treatment ApproachMGUS

Close monitoring (observation)

Smoldering MM

Close monitoring (observation)

If high risk: possible myeloma drugs?

Active myeloma

Initial therapy• Myeloma drugs• High-dose chemotherapy/

stem cell transplantation (option, if possible)

Maintenance optionTherapies for relapsed/refractory myeloma

If bone loss: bisphosphonates

Bone loss: bisphosphonates+

other supportive treatments

Clinical trial participation should be considered.

Hideshima T, Anderson KC. Nature Rev Cancer. 2002;2:927.Hideshima T et al. Blood. 2004;104:607.Hideshima T, Anderson KC. Nat Rev Cancer. 2007;7:585.

Currently Available Therapies Targeting Myeloma Cells in the Bone Marrow Microenvironment

Bone marrowstromal cell

VCAM-1, fibronectinICAM-1 LFA-1 MUC-1

VLA-4

IL-6, VEGFIGF-1, SDF-1BAFF, APRIL,

BSF-3

TNFTGFVEGF

NF-�B

NF-B

Adhesion molecules

NF-B

Smad, ERK

JAK/STAT3

MEK/ERK

PI3-K

GSK-3FKHR

Caspase-9NF-BmTOR

Bad

PKC

Bcl-xLMcl-1

MEK/ERKp27Kip1

NF-BBcl-xL

IAPCyclin-D

MM cell

SurvivalAnti-apoptosis

Cell cycle

SurvivalAnti-apoptosis

Cell cycle

Proliferation

SurvivalAnti-apoptosis

Akt

Migration

ProliferationAnti-apoptosis

Cytokines

Raf

FGFR3

Adhesion

CD40

CS1

BAFF-R

VEGFR

,

Cytokines, growth factors

Targeting MM cell

Targeting MM cell and BM micro-

environment

Proteasome inhibitors: Velcade, Kyprolis, Ixazomib

IMiDs:Thalomid, Revlimid,

PomalystHDAC inhibitor:

Farydak, Ricolinostat

CD138

IGF1R

CD38

C56

T

NK

M

Antibodies to cell surface targets:

DaratumumabElotuzumabIsatuximab

1962 1983 1986 1996 2012

Evolution of Multiple Myeloma Treatment: 10 New Drugs Approved in ≤12 Years

1984 2003 2006 2007

VAD, vincristine, doxorubicin, dexamethasone; IMiD, immunomodulatory drug; HDAC, histone deacetylase.

2013

Chemotherapy

Steroid Transplant

IMiD

Bone supportProteasome inhibitor

HDAC inhibitor

2015

Conventional Therapy Novel Therapy

BisphosphonatesMelphalan

and prednisone

VAD

High-dose dexamethasone

High-dose chemotherapy with

autologous stem cell support

Kyprolis

High-dose melphalan

High-dose chemotherapy with autologous bone

marrow transplant

Velcade

Thalomid

Revlimid

Doxil

Pomalyst

Farydak

Ninlaro

2016

Empliciti

Darzalex

Monoclonal Antibody

Novel Therapies and Immunotherapy

Continuing Evolution of Multiple Myeloma Treatment: New Classes and Targets

PLD, peglylated liposomal doxorubicin; IMiD, immunomodulatory drug; HDAC, histone deacetylase; KSP, kinesin spindle protein, SINE, selective inhibitor of nuclear export*Not yet FDA-approved; only available in clinical trials†Treatments studied in MMRC trials‡FDA-approved for a non-MM indication

20122003 2006 2007 2013 2015 2016+

Doxil

Kyprolis

Velcade

Thalomid

Revlimid

Pomalyst

Farydak Isatuximab*†

Atezolizumab* †

Nivolumab‡

Vaccines*

Ninlaro

Darzalex

Empliciti

Pembrolizumab‡

Filanesib*

CAR-T*

Selinexor* †

Oprozomib*

Proteasome inhibitor

IMiD

Chemotherapy

Vaccines

Adoptive T cell therapy Checkpoint inhibitors

HDAC inhibitor Monoclonal Antibody SINE

KSP inhibitor

Selected Novel Drugs Being Explored in Clinic Trials

Third/ Fourth-generation

agents

Proteasome inhibitors

IMIDs

marizomib, oprozomib, ixazomib

CC-220

Novel classes of

Therapy

Monoclonal antibodies anti-CD38, anti–CD-138 conjugate, anti-BCMA conjugate, antiCS1-conjugate

Check Point Inhibitors Durvalumab, Atezolizumab, PembrolizumabNivolumab

BTKi Ibrutinib, AVL-292

HDAC inhibitors panobinostat,* romidepsin, ricolinostatPleiotropic Pathway Modifier CC:122

Kinesin Spindle Inh ARRY

CDK PD0332991, SCH727965, AT7519

BCL antagonist ABT263

HSP90 Ganetespib (STA-9090)

SINE XPO antagonist KPT-330 (Selinexor)

FGFR3 TKI258, MFGR1877S

17p mutated Idasanutlin

Clinical Trials

Advancements in Survival from Multiple Myeloma

Blood (ASH Annual Meeting Abstracts) 2011 118: Abstract 2948; AACR Annual Meeting, April 20, 2016; New Orleans, LA.; Abstract 5231.

• With new biology based medications response rates for newly diagnosed myeloma are now 91 to 98%.

54,963

74,814

2004

2011

People in the United States living with,or in a remission  from Multiple Myeloma

19,851More People

Have Survived

• From 2011 to 2022, expect the number of patients living with myeloma to increase by 55%(from 76,000-119,000), due to improvements in prognosis.

2015

95,874

• New myeloma cases among men and women ages 40 to 79 years will increase by 28% (from 16,000-21,000) by 2022.

Summary

Be an informed and empowered patient!

Multiple myeloma can have numerous effects on the body

Genomics is growing and may lead to personalized treatments

Survival improving because of new drugs and new combinations of drugs

Treatment paradigm will continue to change with the approval of additional novel agents

MMRF Resources

MMRF CoMMunity Gatewaywww.mmrfcommunitygateway.org

Multiple Myeloma Disease Overview brochure

Multiple Myeloma Treatment Overview brochure